Patent GB-1351754-A (GB)
Title: Indenopyrrole derivatives
Inventor: HAYES N F
IPC: C07D209/70
Filed: 1970-07-02
Abstract: 1351754 Indenopyrroie derivatives ALLEN & HANBURYS Ltd 22 June 1971 [2 July 1970] 32120/70 Headings C2C and C2P The invention comprises indenopyrrole derivatives of the Formula I in which R 1  isH, carbamoyl or dialkylcarbamoyl, C 1-6  alkyl or C 2-6  alkenyl optionally substituted with one or more aryl, hydroxy, oxo or substituted amino groups; R 2  and R 3  which may be the same or different, are H, C 1-6  alkyl or OR 1  or O.CO.Alk, wherein Alk is alkyl; R 4  and R 5  which may be the same or different, are H, C 1-6  alkyl or phenyl; and R 6  is H or C 1-6  alkyl, except that when R 4  is C 1-6  alkyl or phenyl R 4  can only be H, and non-toxic pharmaceutically acceptable salts. The compounds in which R 6  is H are prepared by reducing lactams of the Formula III and compounds in which R 6  is other than H by catalytically hydrogenating the indenopyrroles of the formula above, and, if desired, converting the imino hydrogen atom into another group R 1 , and groups R 2  and R 3  to other groups within the meanings above. Lactams of the above Formula III are obtained by cyclizing the corresponding methyl 2,3-dioxo-1-indanacetate-2-ozimes, obtained by reacting amyl nitrite with the appropriate methyl esters of the 3-oxo-1-indanacetic acids of the Formula VI and, if desired, converting the resulting compound in which R 1  is H into a compound in which R 1  is other than H, and/or R 2  and R 3  represent different groups. The methyl esters of the 3-oxo-1-indanacetic acids of the Formula VI above are obtained by esterifying the 3-oxo-1-indenacetic acids resulting from the cyclization of 3-(R 2 ,R 3 -phenyl)glutaric anhydride, obtained by reacting acetic anhydride with the corresponding glutaric acid, which is made by refluxing 2,4-dicyano-3-(R 2 R 3 -phenyl) glutaric acids, resulting from the reaction between the corresponding benzaldehyde and cyanoacetic acid. 1 - Benzyl - 3,3a - dihydro - 5 - methoxyindeno- [2,1-b]pyrrol-2,8(1H,8aH)-dione is prepared by benzylating 3,3a-dihydro-5-methoxyindeno[2,1- b]-pyrrol-2,8(1H,8aH)-dione, obtained by reacting polyphosphoric acid with cis-3-(3-methoxyphenyl)-5-oxo-2-pyrrolidine-carboxylic acid resulting from the decarboxylation of cis-3-(3- methoxyphenyl) - 5 - oxo - 2,2 - pyrrolidine - dicarboxylic acid, which is prepared by reacting diethyl acetamidomalonate with ethyl 3-methoxycinnamate. 1 - Benzyl - 3,3a,8,8a - tetrahydro - 8 - hydroxy- 5 - methory - 8 - phenylindeno[2,1-b]-pyrrol- 2[1H]-one is obtained by reacting phenylmagnesium bromide with 1-benzyl-3,3a-dihydro-5- methoxyindeno[2,1-b]pyrrol-2,8[1H,8H]-dione. 1 - Benzyl - 3,3a,8,8a - tetrahydro - 5 - methoxy- 8 - methylindeno - [2,1-b]pyrrol - 2[1H] - one is prepared by hydrogenating 1-benzyl-3,3a,8,8atetrahydro - 5 - methoxy - 8 - methyleneindeno- [2,1-b]pyrrol-2[1H]-one obtained by reacting the corresponding 2,8-dione with methylmagnesium iodide. 1,8 - Dihydro - 5 - methoxy - 2 - methylindeno- [2,1-b]pyrrole is obtained by decarboxylating 1,8 - dihydro - 5 - methoxy - 2 - methylindeno- [2,1-b]-pyrrole - 3 - carboxylic acid, resulting from the hydrolysis of the ethyl ester thereof, which is made by reacting 2-amino-6-methoxyindan-1-one hydrochloride with ethyl acetoacetate. Diethyl 1-benzyl-1,2,3,3a,8a-hexahydroindeno- [2,1-b]pyrrol-5-yl phosphate is obtained by reacting diethyl phosphite and 1-benzyl-1,2,3,3a- 8,8a-hexahydraindeno[2,1-b]pyrrol-5-ol in the presence of CCl 4  and triethylamine. Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above novel compounds or salts thereof in association with non-toxic pharmaceutically acceptable carriers. The compounds possess analgetic activity.